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Pain, Delirium or “Neuro-irritability”?
Episodes of Inconsolability in Children
with Neurodevelopmental Delay
Stefan J. Friedrichsdorf, MD, FAAP
Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine, Children's
Hospitals and Clinics of Minnesota, Minneapolis/St. Paul, MN
Associate Professor of Pediatrics, University of Minnesota Medical School
[email protected]
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Twitter: @NoNeedlessPain
Appreciate high prevalence of pain children with
neurodevelopmental Delay
Describe main causes of pain in this heterogenous patient
group
Develop a step-by-step treatment approach for neuropathic
pain
What are we talking about?
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Episodes of inconsolability
Cognitively impaired, non-communicating children
Neurodegenerative / metabolic conditions (e.g.
mitochondrial complex 1 deficiency)
Is it Pain...?
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Children with CP: Daily pain 8.1%
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Cognitively impaired, non-communicating children: Daily pain 23.5 %
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Houlihan CM, O’Donnell M, Conaway M, Stevenson RD: Bodyli pain and healthrelated quality of life in children with cerebral palsy. Develop Med Child Neurol 2004, 46:305-10
Stallard P,
Williams L, Lenton S,Velleman R: Pain in cognitively impaired, non-communicating children. Arch Dis Child 2001;85-460-2
275 children with progressive, non-curable genetic, metabolic, or
neurological conditions: Pain 53% [Most of the time: 21.8 %] Steele R, Siden H, Cadell S, et
al. Charting the territory: symptoms and functional assessment in children with progressive, non-curable conditions. Arch Dis Child. Aug 2014;99(8):
754-762.
Wolfe J, Orellana L, Ullrich C et al Symptoms and Distress in Children with Advanced Cancer: Prospective PatientReported Outcomes from the PediQUEST Study, JCO 2015.
Potential Pain Pathologies
• Nociceptive Somatic Pain (Acute)
• Visceral Nociceptive Hyperalgesia
• Neuropathic Pain
• Chronic Pain (Pain beyond expected time of
healing)
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Psycho-social-spiritual Pain
Somatic pain in the neurologically
impaired child (examples)
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HEENT: Headaches,VP shunt malformation, otitis,
corneal abrasion, sinusitis, pharyngitis, dental pain
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MS: Musculoskeletal pain, spasticity, hip dislocation,
fracture, osteomyelitis
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GI: GER, esophagitis, pancreatitis, ulcer, gallstones
RENAL: UTI, nephrolitiasis
PULMO: Aspiration, reactive airway, costochondritis
GU: testicular/ovarian torsion, inguinal hernia
Multimodal (Opioid-sparing) Analgesia
Non-Opioids
• Acetaminophen /
Paracetamol
• NSAIDs
Opioids
Such as:
• Tramadol („weak“)
• Morphine („strong“)
4 WHOPrinciples
• “By the clock”
Integrative
Therapies
Such as:
• Massage
• Distraction
• Deep Breathing
• Biofeedback
• Aromatherapy
• Hypnosis
Invasive
Approaches
• Regional anesthesia
• Neuraxial anesthesia
- Epidural or intrathecal
- Nerve blocks
- Neurolytic blocks
• Intraventricular opioids?
• Percutaneous cervical cordotomy?
Rehabilitation
• Exercise
• Physical Therapy
• Sleep Hygiene
• Occupational Therapy
• Child Life
Respite
Potential Pain Pathologies
• Nociceptive Somatic Pain (Acute)
• Visceral Nociceptive Hyperalgesia
• Neuropathic Pain
• Chronic Pain (Pain beyond expected time of
healing)
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Psycho-social-spiritual Pain
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Visceral Hyperalgesia
Alteration in response to bowel sensory input ->
recruitment of previously silent nociceptors ->
sensitization of visceral afferent pathways
Tricyclic antidepressants (e.g. amitriptyline)
Ca-channel ligand (e.g. gabapentin)
5-HT3 Receptor antagonist (e.g. ondansetron)
Integrative, non-pharmacological therapies
CBT (parents & child)
Aromatherapy
Massage
Music
Terminal Feeding Intolerance?
Feeding to comfort only?
Discontinuation of artificial feeding / medical hydration and
nutrition?
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Potential Pain Pathologies
• Nociceptive Somatic Pain (Acute)
• Visceral Nociceptive Hyperalgesia
• Neuropathic Pain
• Chronic Pain (Pain beyond expected time of
healing)
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Psycho-social-spiritual Pain
Neuropathic Pain
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Pain arising as a direct consequence of a
lesion or disease affecting the
somatosensory system (IASP 2008)
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Grading System: (1) Definite, (2) Probable; (3)
Possible
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(…but, not all lesions in the somatosensory system
lead to neuropathic pain)
Prevalence
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Population prevalence of
pain with neuropathic
characteristics is likely 6.9% 10% van Hecke, O., et al., Neuropathic pain in the general
population: a systematic review of epidemiological studies. Pain,
2014. 155(4): p. 654-62.
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Prevalence of neuropathic
pain in children unclear
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Cancer pain > 12 years:
Metaanalysis (n=22):
Conservative 19%; liberal
estimate: 39% Bennett MI, Rayment
Probably not in infants...?
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Brachial plexus injury in
newborns
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Rats not before P7 to P21,
i.e. 4-5 months in children...
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Damage early on: no
memory...adaptive immune
system...?
C, Hjermstad M, Aass N, Caraceni A, Kaasa S.
Prevalence and aetiology of neuropathic pain in cancer
patients: a systematic review. Pain. 2012 Feb;153(2):
359-65.
Potential Causes Include
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Spinal cord injury: “pain
arising as a direct
consequence of affecting the
somatosensory system”
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Tumor related: direct
tissue and nerve injury;
advanced unresectable solid
tumors
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Phantom limb pain: 60
- 80% of adult patients with
amputation experience
phantom sensations in their
amputated limb, majority are
painful Sherman RA., Sherman CJ, Parker L. Chronic
phantom and stump pain among American veterans: Results of
a survey". Pain. 1984;18: 83–95.
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Autoimmune and
degenerative
neuropathies: GuillainBarré syndrome; CharcotMarie-Tooth disease Walco GA,
Dworkin RH, Krane EJ, LeBel AA, Treede RD. Neuropathic pain
in children: Special considerations. Mayo Clin Proc. 2010;85(3
Suppl):S33-41
Potential Causes Include
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Metabolic neuropathies:
toxic and metabolic neuropathies
(eg, lead, mercury, alcohol,
infection)
Neurodegenerative
disorders: Hereditary
neurodegenerative disorders
(Fabry disease, X-linked
lysosomal disease caused by
deficiency α-galactosidase),
mitochondrial disorders, and
primary erythromelalgia
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Cancer-directed
chemotherapy, including
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Vincristine: 50% painful
peripheral neuropathy, muscle
camps, numbness, tingling
(hand, feet)
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Cisplatin: Paresthesias in
extremities
Neuropathic Pain Mechanisms
Periaqueductal
grey
Thalamus
Central
Sensitization:
Activities in C-Fibers drives
changes in 2nd neuron
dN
2n
on
eur
g
din
en n
sc itio
De nhib
I
Glial activation & cytokine
release
also involved?
Result: áexcitability
and synaptic efficiency
+
+
o
Aδ
Injury induced
accumulation of
Na-channels
=> ectopic firing
rC
Injury
fib
er
Reduced
inhibition in
Dorsal Horn
Altered Synaptic Transmission:
Ca-channel
[α-2-δ dysfunction?)
+
+
Peripheral Sensitization:
Response to Tissue Injury
Neuropathic Pain Assessment
Scrubs
Neuropathic Pain Assessment
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Currently there are no validated
neuropathic pain scales for
children < 18 years
Adults
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NPS® Neuropathic Pain
Scale - 12 items
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http://www.mapi-research.fr/
t_03_serv_dist_Cduse_nps.h
tm Galer BS, Jensen MP. Development and preliminary
validation of a pain measure specific to neuropathic pain: the
Neuropathic Pain Scale. Neurology. 1997 Feb;48(2):332-8
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Pain Quality Assessment
Scale (PQAS) - 20 items
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http://www.mapi-research.fr/
t_03_serv_dist_Cduse_pqas.htm
Jensen, M.P. (in press). Pain assessment in clinical trials. In D. Carr &
H. Wittink (Eds.), Evidence, outcomes, and quality of life in pain
treatment. Amsterdam: Elsevier.
Neuropathic Pain Assessment
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Evaluate for
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Paroxysmal pain
Paresthetic or
dysesthetic sensation
Use age-appropriate
pediatric scales for
acute pain instead,
including
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VAS (or numerical pain
rating scale) 0-10
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Faces scales-revised
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FLACC
CRIES
COMFORT
Descriptions might
include:
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numbness
tingling
burning
electric-like
shooting
Pain in children with
impaired communication
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Non-communicating
Children’s Pain
Checklist - Revised
(NCCPC-R);
postoperative Version
(NCCPC-PV) (Breau,
2002)
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Pediatric Pain Profile
(PPP) (Hunt, 2003)
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r-FLACC (Malviya
2006)
Multimodal Analgesia
Children’s “Comfort Promise” - We do everything possible to prevent and treat pain
Multimodal (Opioid-sparing) Analgesia
Non-Opioids
• Acetaminophen /
Paracetamol
• NSAIDs
Invasive
Approaches
Opioids
Such as:
• Regional anesthesia
• Neuraxial anesthesia
- Epidural or intrathecal
- Nerve blocks
- Neurolytic blocks
• Tramadol („weak“)
• Morphine („strong“)
4 WHOPrinciples
• Intraventricular opioids?
• Percutaneous cervical cordotomy?
• “By the clock”
Integrative
Therapies
Such as:
• Massage
• Distraction
• Deep Breathing
• Biofeedback
• Aromatherapy
• Hypnosis
Adjuvants
Such as:
Rehabilitation
• Exercise
• Physical Therapy
• Sleep Hygiene
• Occupational Therapy
• Child Life
Respite
• Alpha-Agonist
• Gabapentinoids
• TCA/Antidepressants
• NMDA-Antagonists
• Na-channel blockers
• Antispasmodics
• Benzodiazepines
• Corticosteroids
• Muscle relaxants
• Radiopharmaceuticals
• Bisphosphonates
Pharmacotherapy for neuropathic pain in adults
Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. The Lancet.
Neurology. Feb 2015;14(2):162-173.
Medication (# of placebo
# of
controlled studies)
participants
Pain
Relief
Placebo
NNT
NNH
Botox A (4)
137
60%
6%
1.9
ns
TCAs (15)
948
45.9%
17.9%
3.6
13.4
Strong Opioids (7)
838
51. 9 %
26.2%
4.3
11.7
Tramadol (6)
741
46.3%
26.6%
4.7
12.6
Gabapentin (14)
3503
34.7%
20.3%
6.3*
25.6
Serotoninenoradrenaline reuptake
inhibitor (10)
2541
43.4%
28.3%
6.4
11.8
Pregabalin (25)
5940
38.5%
24%
7.7
13.9
Capsaicin 8% (6)
2073
35.9%
27.4%
10.6
ns
* extended release gabapentin NNT: 8.; NNH 31.9
ns=non significant
Pediatric Relevance?
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Adults usually suffer from
diabetic neuropathy,
trigeminal neuralgia,
shingles, HIV neuropathy
etc.
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Children do not
Pain in Children with
Mitochondrial Diseases?
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Animal model: Mitochondria play
important role in inflammatory
and neuropathic pain
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Inhibition of 2 key mitochondrial
functions (ATP generation,
reactive oxygen species) ->
attenuate protein kinase
C[epsilon] dependent form of
mechanical hyperalgesia
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Dorsal root ganglion:
Accumulation of mitochondria
(in vitro by nerve growth factor)
Chu C, Levine E, Gear RW, Bogen O, Levine JD. Mitochondrial
dependence of nerve growth factor-induced mechanical
hyperalgesia. Pain. 2011 Aug;152(8):1832-7.
9-year old E.T.
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2-year old girl (Brown-Vialetto-Van Laere Syndrome)
Global motor-neurodevelopmental delay with loss of some milestones
Respiratory chain complex-1 deficiency mitrochondropathy
De novo 10q minus deletion
Mild hypoplasia of corpus callosum, gliosis of posterior left frontal white matter, posterior limb of
internal capsule
Cortical and visual impairment
Central hyperventilation syndrome with illness-triggered apnea
Chief complaints:
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Episodes of inconsolability/pain for hours at night;Vomiting; Apnea
Workup completely negative
Start: Tramadol, amitriptyline (-> nortriptyline), PRN acetaminophen, ibuprofen
Management of Neuropathic Pain
in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach
(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep
disturbances). Psychological Therapies.
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
Integrative, rehabilitative &
supportive therapies
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Expected part of treatment
protocol; Age-appropriate
modalities include
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Behavioral (deep breathing,
imagery, hypnosis, smartphone/tablet “apps”)
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Physical (massage, TENS,
comfort positioning, allowing
family for close contact/touch)
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Acupressure, acupuncture,
aromatherapy
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Rehabilitation (physical
therapy, occupational therapy)
Integrative Pain & Symptom
Management
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A Pediatrician’s Top 10
Apps for Distraction &
Pain Management http://
NoNeedlessPain.org
In other words...
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Adult data: Despite best of care
and sequential trials of
pharmacological therapies:
40-60% of patients remain
unrelieved or inadequately
relieved Dwokin et al. Pain 2007, 132:237-51
In the treatment of medium to
severe neuropathic pain in
children medications alone
are not sufficient:
Management likely inefficient
without:
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PT/OT
Integrative Therapies
Psychological therapies
Management of Neuropathic Pain
in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach
(3) Regional anesthesia, if appropriate
(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep
disturbances). Psychological Therapies.
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
Regional anesthesia approaches to
pain management in PC
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Regional anesthesia:
pediatric knowledge limited
to case reports and case
series:
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Neurolytic
Sympathectomy:
Amr YM,
Makharita MY. Neurolytic sympathectomy in the management of cancer paintime effect: a prospective, randomized multicenter study. J Pain Symptom
Manage. Nov 2014;48(5):944-956 e942.
Rork, J.F., C.B. Berde, and R.D. Goldstein, Regional anesthesia
approaches to pain management in pediatric palliative care: a review of current knowledge.
J Pain Symptom Manage, 2013. 46(6): p. 859-73.
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central neuraxial infusions
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neurolytic blocks
peripheral nerve and plexus
blocks or infusions
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RCT (n=109) inoperable
abdominal or pelvic cancer:
better pain control, less
opioid consumption, and
better quality of life
implanted intrathecal ports &
pumps for baclofen, opioids, local
anesthetics, and other adjuvants
Management of Neuropathic Pain
in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach
(4) NEW (!) onset: Opioid analgesics [consider Tramadol or Methadone] plus
NSAID
(3) Regional anesthesia, if appropriate
(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep
disturbances). Psychological Therapies.
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
NSAIDs for Neuropathic Pain
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No RCTs
Finnerup NB, Attal N, Haroutounian S, et
al. Pharmacotherapy for neuropathic pain in adults: a
systematic review and meta-analysis. The Lancet.
Neurology. Feb 2015;14(2):162-173.
NSAIDs are commonly prescribed
for neuropathic pain Dieleman JP, Kerklaan J,
Huygen FJ, Bouma PA, Sturkenboom CJ. Incidence rates and
treatment of neuropathic pain conditions in the general population.
Pain 2008;137:681-8.
NSAIDs are so widely viewed as
being ineffective for neuropathic
pain that no major guidelines even
mention them in their
algorithm.Attal N, Cruccu G, Baron R, Haanpää M, Hansson
P, Jensen TS, et al. EFNS guidelines on the pharmacological treatment
of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113-e88.
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Preclinical and clinical studies have
demonstrated efficacy for NSAIDs
in neuropathic pain states Vo T, Rice AS,
Dworkin RH. Non-steroidal anti-inflammatory drugs for neuropathic
pain: how do we explain continued widespread use? Pain
2009;143:169-71.; Cohen KL, Harris S. Efficacy and safety of
nonsteroidal anti-inflammatory drugs
Opioids for Neuropathic Pain
“Weak” opioids (=
multimechanism)
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“Strong” Opioids
Tramadol NNT 4.7; NNH
6.3 Finnerup NB, Attal N, Haroutounian S, et
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Attal N, Haroutounian S, et al. Pharmacotherapy
for neuropathic pain in adults: a systematic review
and meta-analysis. The Lancet. Neurology. Feb
2015;14(2):162-173.
al. Pharmacotherapy for neuropathic pain in
adults: a systematic review and meta-analysis. The
Lancet. Neurology. Feb 2015;14(2):162-173.
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Tapentadol? Bias; NNT
10.2
Morphine, oxycodone
NNT 4.3; NNH 11.7 Finnerup NB,
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No additional benefit > 180 mg
morphine equivalent
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Cochrane analysis: Oxycodone
NOT effective as a pain medicine
in diabetic neuropathy or
postherpetic neuralgia Gaskell H, Moore
RA, Derry S, Stannard C. Oxycodone for neuropathic pain
and fibromyalgia in adults. Cochrane Database Syst Rev.
2014;6:CD010692.
Nociceptive Pathways & Primary Sites of Action of Analgesics
Thalamus
on
eur
dN
2n
Aδ
or
C
Opioids
er
fib
Acetaminophen
(Paracetamol)
NSAIDs
Injury
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
Descending pathways that modulate transmission of nociceptive
signals originate in periaqueductal gray, locus coeruleus, anterior
cingulate gyrus, amygdala & hypothalamus: are relayed through
brainstem nuclei in the PEG and medulla to spinal cord.
dN
2n
on
eur
g
in
nd o n
ce iti
es ib
D nh
I
+
Integrative
(non-pharmacological)
therapies
Inhibitory transmitters involved in these pathways incl.
norepinephrine, 5-hydroxytryptamine, dopamine, & endogenous
opioids.
o
Aδ
rC
fib
Opioids
er
Injury
Acetaminophen
(Paracetamol)
NSAIDs
Management of Neuropathic Pain
in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach
(5) Tricyclic Antidepressant (or gabapentinoid) ± low-dose ketamine
(4) NEW (!) onset: Opioid analgesics [consider Tramadol or Methadone] plus
NSAID
(3) Regional anesthesia, if appropriate
(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep
disturbances). Psychological Therapies.
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
Amitriptyline
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NNT: 3.6; NNH: 13.4
Finnerup NB, Attal
N, Haroutounian S, et al. Pharmacotherapy for
neuropathic pain in adults: a systematic review and metaanalysis. The Lancet. Neurology. Feb 2015;14(2):162-173.
No dose-response effect
Nortriptyline: only 1 study
Efficacy of TCA in central pain Rintala
DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG.
Comparison of the effectiveness of amitriptyline and gabapentin on
chronic neuropathic pain in persons with spinal cord injury. Archives
of physical medicine and rehabilitation.. 2007 Dec;88(12):1547-60.
•
2 studies (high effect size): no
effect of amitriptyline in HIV
neuropathy Kieburtz K, Simpson D,Yiannoutsos C, Max
MB, Hall CD, Ellis RJ, et al. A randomized trial of amitriptyline and
mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial
Group 242 Protocol Team. Neurology. 1998 Dec;51(6):1682-8. Shlay
JC, Chaloner K, Max MB, Flaws B, Reichelderfer P, Wentworth D, et
al. Acupuncture and amitriptyline for pain due to HIV-related
peripheral neuropathy: a randomized controlled trial. Terry Beirn
Community Programs for Clinical Research on AIDS. JAMA.1998
Nov 11;280(18):1590-5.
Tricyclic antidepressants
(TCA)
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Relieve various neuropathic pain
2 studies: no effect of
amitriptyline & nortriptyline in
chemotherapy-induced
neuropathy (pain not primary
outcome) Hammack JE, Michalak JC, Loprinzi CL, Sloan
•
JA, Novotny PJ, Soori GS, et al. Phase III evaluation of nortriptyline
for alleviation of symptoms of cis-platinum-induced peripheral
neuropathy. Pain. 2002 Jul;98(1-2):195-203. Kautio AL, Haanpaa M,
Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapyinduced neuropathic symptoms. Journal of Pain and Symptom
Management. 2008 Jan;35(1):31-9.
Secondary amine TCAs
(nortriptyline and desipramine)
better tolerated than tertiary
amine TCAs (amitriptyline and
imipramine) with comparable
analgesic efficacy Max, N Eng J Med
1992,326:1250-6; Rowbotham, J Pain 2005,6:741-6; Watson,
Neurology 1998,51:1166-71
Amitriptyline (or
Nortriptyline)
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Dosage: initial 0.1 mg /kg ->
titrate to 0.4 mg/kg p.o., [max.
20-25 mg] (usually not up to 1-2
mg/kg/day) once at night -
•
wean: decrease gradually!
Effect: days - weeks; depends on
length of symptoms
•
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Adverse effects: arrhythmia: EKG
(QTc, WPW?), anticholinergic /
antihistamine (dry mouth,
constipation, blurred vision,
sedation)
Desipramine: anecdotal evidence
of sudden death in children Amitai Y,
Frischer H: Excess fatality from desipramine in children and
adolescents. J Am Acad Child Adolesc Psychiatry 2006. 45(1):54-60
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
TCA
SSRIs
Methadone
Tramadol
o
eur
dN
2n
n
g
din
en n
sc itio
De nhib
I
+
Integrative
(non-pharmacological)
therapies
Aδ
or
C
r
e
fib
Opioids
Tricyclic
Antidepressants:
(+) Opioid analgesia via
serotoninergic mechanism at
brainstem
Acetaminophen
(Paracetamol)
NSAIDs
Injury
Management of Neuropathic Pain
in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach
(6) Tricyclic Antidepressant and gabapentinoid
(5) Tricyclic Antidepressant (or gabapentinoid) ± low-dose ketamine
(4) NEW (!) onset: Opioid analgesics [consider Tramadol or Methadone] plus
NSAID
(3) Regional anesthesia, if appropriate
(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep
disturbances). Psychological Therapies.
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
Gabapentinoids: Ca-channel α2-δ ligands
Voltagegated Cachannel
G
α2-δ subunit
[dysfunction?/upregulation role in neuropathic
pain]
Postsynaptic
nerve
terminal
Presynaptic
nerve
terminal
Glutamate Substance P
Gabapentin
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Gabapentin: NNT: 6.3; NNH:
25.6
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Extended-release
gabapentin: NNT 8.3; NNH
31.9 Finnerup NB, Attal N, Haroutounian S, et al.
•
Pharmacotherapy for neuropathic pain in adults: a
systematic review and meta-analysis. The Lancet.
Neurology. Feb 2015;14(2):162-173.
•
No dose-response effect
15 studies (1468 participants)
(post-herpetic neuralgia, diabetic
neuropathy, cancer related
neuropathic pain, phantom limb
pain, Guillain Barré syndrome,
spinal chord injury pain, various
neuropathic pains) Wiffen PJ, McQuay
HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic
pain. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005452.
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42% improved compared to 19%
on placebo
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NNT for effective pain relief in
diabetic neuropathy 2.9; post
herpetic neuralgia 3.9
Pregabaline
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Efficacy worse than gabapentin
•
Schifitto G, Clifford DB, Murphy TK, Durso-De Cruz E, Glue P, et al.
Pregabalin for painful HIV neuropathy: a randomized, double-blind,
placebo-controlled trial. Neurology. 2010 Feb 2;74(5):413-20.; (2)
Kim JS, Bashford G, Murphy TK, Martin A, Dror V, Cheung R. Safety
and efficacy of pregabalin in patients with central post-stroke pain.
Pain. 2011 May;152(5):1018-23.
NNT: 7.7; NNH: 13.9
Finnerup NB, Attal
N, Haroutounian S, et al. Pharmacotherapy for
neuropathic pain in adults: a systematic review and
meta-analysis. The Lancet. Neurology. Feb 2015;14(2):
162-173.
•
Dose-response (600mg/day more
effective than 300 mg/day)
•
Linear (pregabalin) versus nonlinear (gabapentin) bioavailability:
Clinical relevance unclear.
Negative RCTs: HIV neuropathy;
central post-stroke pain (1) Simpson DM,
•
Adverse effects include: Weight
increase, dizziness, somnolence,
blurred vision, life-threatening
angioedema (face, mouth, larynx)
- careful concurrent
administration with ACE
inhibitors
Children with impairment
of CNS
•
Gabapentin appears to be an
effective treatment for
children with severe
impairment of the CNS and
recurrent pain behaviors,
including intermittent changes
in muscle tone. Hauer JM, Solodiuk JC.
Gabapentin for management of recurrent pain in 22
nonverbal children with severe neurological impairment: a
retrospective analysis. J Palliat Med. May 2015;18(5):453-456.
Gabapentin
•
•
•
Pediatric Dosage: gradually
increasing from 3-5 mg/kg/
dose TID to 10-20mg/kg/dose
TID, max. 1,200 mg/dose TID
Infants: 4.5 mg PO Q6h
(titrated to max. 15 mg Q6h)
[Extended release: 300 -> 1800
mg Qday: No pediatric data;
NNT worse]
Example: 10-year-old girl, 30 kg
Day 1:
100 mg once daily
Day 2:
100 mg BID
Day 3:
100 mg TID
Day 4: 100-100-200 mg
…
Day 9:
300 mg TID
•
•
wean: decrease gradually x
1-2 weeks!
Effect: days - weeks
•
Adverse effects include: ataxia,
nystagmus, myalgia,
hallucination, dizziness,
somnolence, aggressive
behaviors, hyperactivity,
thought disorder, (peripheral
edema)
Other Antiepileptic Drugs
•
Most studies negative Finnerup
•
Poorest safety profile:
•
NB, Attal N, Haroutounian S, et al.
Pharmacotherapy for neuropathic pain in adults: a
systematic review and meta-analysis. The Lancet.
Neurology. Feb 2015;14(2):162-173.
•
Topiramate NNT 6;
NNH 6.3
•
zonisamide NNH 2.0
oxcarbazepine /
carbamazepine NNH
5.5
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
TCA
SSRIs
Methadone
Tramadol
on
eur
dN
2n
g
in
nd on
ce iti
es ib
D nh
I
+
Integrative
(non-pharmacological)
therapies
Combination:
Amitriptyline &
Gabapentin
Aδ
or
C
er
fib
Inhibitors of excitatory
glutamate systems:
Gabapentin/Pregabalin
Carbamazepine*
Valproate
Injury
Acetaminophen
(Paracetamol)
Opioids
NSAIDs
Management of Neuropathic Pain
in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach
(7) Lidocain patch (if localized pain).
(6) Tricyclic Antidepressant and gabapentinoid
(5) Tricyclic Antidepressant (or gabapentinoid) ± low-dose ketamine
(4) NEW (!) onset: Opioid analgesics [consider Tramadol or Methadone] plus
NSAID
(3) Regional anesthesia, if appropriate
(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep
disturbances). Psychological Therapies.
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
Sodium channels are involved in
pain...
•
After nerve injury, expression of
some Na+ channels increases de
novo, the expression of others
diminishes, and some translocate
into different cellular
compartments Levinson, S.R., S. Luo, and M.A.
Henry, The role of sodium channels in chronic pain. Muscle
Nerve, 2012. 46(2): p. 155-65.
•
The proliferation of heterotopic
sodium channels, such as Nav1.3,
Nav1.7, and Nav1.8, may lower
the stimulation threshold and
provoke ectopic discharge,
resulting in spontaneous pain.
Cohen, S.P. and J. Mao, Neuropathic pain: mechanisms and their
clinical implications. BMJ, 2014. 348: p. f7656.
Topical Lidocaine
•
> 3 weeks: 3 studies (1 positive, 2
negative) Finnerup NB, Attal N, Haroutounian S, et
•
al. Pharmacotherapy for neuropathic pain in adults: a
systematic review and meta-analysis. The Lancet.
Neurology. Feb 2015;14(2):162-173.
•
Produces selective, but
incomplete block of A-delta
and C fibers Krumova EK, Zeller M,Westermann
A, Maier C. Lidocaine patch (5%) produces a selective, but
incomplete block of Adelta and C fibers. Pain. 2012 Feb;
153(2):273-80.
Cochrane analysis: Small, shortterm trials indicate topical
lidocaine may be effective in
treating neuropathic pain; safety &
tolerability were good in all cases
Derry S, Wiffen PJ, Moore RA, Quinlan J. Topical lidocaine
for neuropathic pain in adults. Cochrane Database Syst
Rev. 2014;7:CD010958.
Topical Lidocaine 5%
patch
•
RCT (n=87) effective adjunct
in post-operative (knee
replacement) pain
management Nafissi A: Lidoderm's
effectiveness in reducing pain in post-operative unilateral
knee replacements patients. 30th Annual Scientific Meeting
of the American Pain Society May 2011 (Poster)
•
•
•
For localized pain only
Patch can be cut to fit
12 hours on/12 hours off
[possibly longer?]
•
Not with severe hepatic
dysfunction
•
Side effects include skin
problems (such as irritation
and redness)
IV Lidocaine - Pediatric
Experience
•
Nausea after 4 days?
Neuropathic Pain: 1mg/kg over
5 min, then 1mg/hr - target:
2-5 mcg/mL Krane E, Leong M, Golianu B, Leong
Y. Treatment of Pediatric Pain with Nonconventional
Analgesics. In: Schechter N, Berde C,Yaster M, editors. Pain in
infants, children, and adolescents. Philadelphia: Lippincott
Williams & Wilkins; 2003. p. 225-40
•
Side Effects:Allergic reaction
(serious, but rare), dose
related: numbness around
mouth, dizziness, slurring of
speech, hallucinations, muscle
twitches, seizures R, Paice JA. How to
•
Case Series (n=5) after anti-GD2
antibody therapy in children with
neuroblastoma: 1mg/kg/hr
Wallace MS,
Lee J, Sorkin L, Dunn JS,Yaksh T,Yu A. Intravenous lidocaine:
effects on controlling pain after anti-GD2 antibody therapy in
children with neuroblastoma--a report of a series. Anesthesia
and analgesia. 1997 Oct;85(4):794-6.
•
•
initiate and monitor infusional lidocaine for severe and/or
neuropathic pain. The journal of supportive oncology. 2004
Jan-Feb;2(1):90-4.
Case report; end-of-life cancer
care: 2.1-3 mg/kg/hr Massey GV, Pedigo S,
Dunn NL, Grossman NJ, Russell EC. Continuous lidocaine
infusion for the relief of refractory malignant pain in a
terminally ill pediatric cancer patient. Journal of pediatric
hematology/oncology. 2002 Oct;24(7):566-8.
Case report 5-year-old girl,
meningitis caused by malignant Tcell lymphoma with difficult to
treat neuropathic pain; IV
lidocaine (9.3–14 mcg/kg/min)
J Palliat
Med. 2012 Jun;15(6):719-22. doi: 10.1089/jpm.2011.0097. Epub
2012 Mar 8. Continuous intravenous infusion of ketamine and
lidocaine as adjuvant analgesics in a 5-year-old patient with
neuropathic cancer pain. Kajiume T, et al.
Management of Neuropathic Pain
in Pediatrics Suggested “Non-Evidence-based” Step-by-Step Approach
(8) NMDA-receptor-channel blocker [ α- agonist? IV lidocaine? Botox A?
benzodiazepine? SNRI? Capsaicin?]
(7) Lidocain patch (if localized pain).
(6) Tricyclic Antidepressant and gabapentinoid
(5) Tricyclic Antidepressant (or gabapentinoid) ± low-dose ketamine
(4) NEW (!) onset: Opioid analgesics [consider Tramadol or Methadone] plus
NSAID
(3) Regional anesthesia, if appropriate
(2) Integrative therapies & Rehabilitation: manage comorbidities (anxiety, sleep
disturbances). Psychological Therapies.
(1) Identify and treat underlying disease process (radiation?) (corticosteroids?)
Opioid induced tolerance and
hyperalgesia
mu-receptor
Gi/o proteins
Opioid induced tolerance and
hyperalgesia
Opioid
mu-receptor
stimulation
Inhibition of Ca
channels: â
neurotransmitter
release
Genes
Alter response
characteristics of
neuron => Suppress
neuronal
excitability
uncoupling
Gi/o proteins
activation
generation
Protein Kinase-C
Membrane
Hyperpolarization
(K+ channel)
Other
neuromodulators
Opioid induced tolerance and
hyperalgesia
Opioid
mu-receptor
Gi/o proteins
activation
Proteine Kinase-C
activation
NMDA-channel
Chen L, Nature 1992; 365:521-3
NMDA-Receptor Channel Blocker
Na+
Ca2+
Glycine
recognition site
Glutamate
recognition site
Cell membrane
Mg2+
K+
1. Membrane potential at resting level
-> channel blocked by Magnesium
Excitatory NMDA (N-Methyl-d-Aspartat) Receptor channel complex
NMDA-Receptor Channel Blocker
Glycine
recognition site
Na+
Ca2+
Glutamate
recognition site
Cell membrane
K+
2. Membrane potential changed as a result of áexcitation
â Opioid-sensitivity
- Central (dorsal horn) sensitization
- radiation of pain
- spontaneous pain
- Hyperalgesia, allodynia
NMDA-Receptor Channel Blocker
Glycine
recognition site
Na+
Ca2+
Glutamate
recognition site
Cell membrane
Ketamine
K+
3. Phencyclidin (PCP) - binding sites [uncompetitive NMDA receptor
antagonists with moderate affinity]
- Ketamine
- Methadone
- Levorphanol
- (Dextrometorphane?)
NMDA-Receptor Channel Blocker
•
•
NMDA receptors in
supraspinal facilitatory sites
(such as rostral ventromedial
medulla, nucleus
gigantocellularis) maintain
non-inflammatory muscle
pain in animal model Da Silva LF,
Desantana JM, Sluka KA. Activation of NMDA receptors in
the brainstem, rostral ventromedial medulla, and nucleus
reticularis gigantocellularis mediates mechanical
hyperalgesia produced by repeated intramuscular injections
of acidic saline in rats. J Pain. 2010 Apr;11(4):378-87.
•
•
Central NMDA receptors
topical 10% ketamine
(compounded in pluronic
lecithin organogel) reduced
allodynia in CRPS. Adult RCT
(n=20) Finch PM, Knudsen L, Drummond PD.
Reduction of allodynia in patients with complex regional
pain syndrome: A double-blind placebo-controlled trial of
topical ketamine. Pain. 2009 Nov;146(1-2):18-25.
•
Evidence:
Dextromethorphan (6),
Memantine (5), Mg (1): NNT
5.0; NNH 9.4 Finnerup NB, Attal N,
Haroutounian S, et al. Pharmacotherapy for neuropathic
pain in adults: a systematic review and meta-analysis.
The Lancet. Neurology. Feb 2015;14(2):162-173.
Peripheral NMDA
receptors
•
No ketamine
Ketamine
•
Dissociative anesthetic which has
analgesic properties in subanesthetic doses.
•
Racemic mixture [S(+)enantiomer (Analgesia, GA); R(-)enantiomer (bronchodilatation,
nightmares)]
•
Sedative-HypnoticDissociative Dosing: 1-2 mg/
kg/dose IV
•
Analgesic (subanesthetic)
Dosing: IV: 1-5 mcg/kg/min
[=0.06-0.3 mg/kg/hr]
•
PO: 0.2-0.5 mg/kg TID-QID
and PRN (sc, sl, intranasal, pr,
spinally)
•
Adverse effects: intracranial
hypertension, tachycardia,
psychotomimetic phenomena
(euphoria, dsyphoria, vivid
hallucinations) -> at lowdose??
Low-dose Ketamine
•
Action which may contribute to
analgesic effect: Meller S, Pain 1996. 68:435-6
•
•
Cholinergic transmission
•
•
μ, δ, κ - opioid-like effect
Noradrenergic / serotinergic
re-uptake inhibition
Interactions with other Na-/
Ca- channels
Low-dose Ketamine - Pediatric
Evidence
•
no RCT‘s, few case reports:
•
n = 11,
terminal cancer, age 3-17
Finkel JC, J Pain 2007; 8(6):515-21
•
Starting dose: 0.1-0.2 mg/kg/
hr (max 1 mg/kg/hr)
•
•
Lorazepam 0.025 mg/kg BID
•
n = 8/11: â Pain; â Opioid
requirements (28-100%)
No psychotropic side effects,
no hallucinations
•
5-year-old girl, meningitis caused
by malignant T-cell lymphoma
with difficult to treat neuropathic
pain. IV lidocaine (9.3–14 mcg/kg/
min) and later ketamine (2 mcg/
kg/min) in combination with
fentanyl (0.8-1.2 mcg/kg/hr)
provided good analgesia without
significant side effects for the last
20 days of her life. J Palliat Med. 2012 Jun;15(6):
719-22. doi: 10.1089/jpm.2011.0097. Epub 2012 Mar 8. Continuous
intravenous infusion of ketamine and lidocaine as adjuvant
analgesics in a 5-year-old patient with neuropathic cancer
pain.Kajiume T, Sera Y, Nakanuno R, Ogura T, Karakawa S,
Kobayakawa M, Taguchi S, Oshita K, Kawaguchi H, Sato T, Kobayashi
M.
Ketamine
•
Short-term ‘burst’ treatment
with ketamine may have longterm benefit Jackson K, J Pain Sympt Managem 2001;
22: 834-42; Mitchell A, Pain Society Annual Scientific Meeting 2001,
Poster 42: 50.
•
Prevents analgesic tolerance to
TENS (in rats) Priyanka MH, J Pain 2008, 9(3):
•
Anti-depressant mechanism: upregulation of mammalian target
of rapamycin (mTOR). Li N, Lee B, Liu RJ,
Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse
formation underlies the rapid antidepressant effects of NMDA
antagonists. Science. 2010 Aug 20;329(5994):959-64. May cause
acceleration of tumor growth? Shor B, Gibbons JJ, Abraham RT,Yu
K. Targeting mTOR globally in cancer: thinking beyond rapamycin.
Cell Cycle. [Review]. 2009 Dec;8(23):3831-7.
217-25
•
Low-dose: Effective rapid acting
anti-depressant? Thangathurai D, Roby J, Roffey P.
Treatment of resistant depression in patients with cancer with low
doses of ketamine and desipramine. J Palliat Med. 2010 Mar;13(3):
235.
Stefanczyk-Sapieha L, Oneschuk D, Demas M. Intravenous
ketamine "burst" for refractory depression in a patient with
advanced cancer. J Palliat Med. 2008 Nov;11(9):1268-71. Kollmar
R, Markovic K, Thurauf N, Schmitt H, Kornhuber J. Ketamine
followed by memantine for the treatment of major depression.
Aust N Z J Psychiatry. 2008 Feb;42(2):170.
Ketamine
• Steady-state oral/parenteral ratio unclear
• Bio-availibilty 93% IM/IV; 20% PO
• Ketamine -> norketamine
• Potency ketamine: norketamine 3:1 (anesthetic); 1:1 (analgesic)
• Plasma half-life: ketamine 1-3 hrs; norketamine 12 hrs
• Maximum blood concentration of norketamine: oral > IV
•Domino E, Clinical Pharm Therapeut 1984, 36:645-53; Clements JA, J Pharm Scienc 1982,71:539-42
• Estimated at 1:1- 1:3 (i.e. 1mg IV = 1-3 mg PO)
Benitez-Rosario MA, Salinas-Martin A, GonzalezGuillermo T, Feria M. A strategy for conversion from subcutaneous to oral ketamine in cancer pain patients: effect of a 1:1 ratio. Journal of Pain and Symptom
Management. 2011 Jun;41(6):1098-105.
Other Adjuvant Analgesics / Coanalgesics
Benzodiazepines (incl. diazepam, lorazepam, midazolam)
✤
Mechanisms of action: gamma-aminobutyric acid (GABA) receptors
✤
✤
✤
Potentiation of GABA-mediated transmission: sedative, anxiolytic, and
anticonvulsant actions
GABA-agonist activity in the limbic cortex: amnestic property Cohen, I.,
Gallagher, TJ, Pohlman, AS, et al., Management of the agitated intensive care
unit patient. Critical Care Medicine, 2002. 30(1): p. S97-S123.
Flumazenil, a competitive antagonist, can rapidly reverse (some of) the
effects of benzodiazepines.
SNRI
•
•
NNT: 6.4; NNH: 11.8
Finnerup
NB, Attal N, Haroutounian S, et al.
Pharmacotherapy for neuropathic pain in
adults: a systematic review and meta-analysis.
The Lancet. Neurology. Feb 2015;14(2):
162-173.
Duloxetine, venlafaxine
Nociceptive Pathways & Primary Sites of Action of Analgesics
Periaqueductal
grey (endorphins)
Thalamus
TCA
SSRIs
Methadone
Tramadol
dN
2n
Stimulation of inhibiting GABA
system
Baclofen
Benzodiazepines
Valproate
on
eur
g
din
en n
sc itio
De nhib
I
+
Integrative
(non-pharmacological)
therapies
Aδ
or
C
er
fib
Inhibitors of excitatory
glutamate systems:
Gabapentin/Pregabalin
Carbamazepine*
Valproate
NMDA-Channel Blockers
Ketamine
Acetaminophen
Methadone
(Paracetamol)
Opioids
NSAIDs
Injury
Sodium-channel
blockade
carbamazepine*
lidocaine
α-Adrenergic Agonists
Analgesic effect?
✤
✤
Postsynaptic alpha-2-adrenergic & mu-opioid receptors activate the same
K-channel via inhibitory Gi/0 -proteins
Presynaptic alpha-2-adrenoreceptors reduce neurotransmitter release by
inhibiting calcium influx Ruffolo, R.R., Jr., et al., Structure and function of alpha-adrenoceptors. Pharmacol Rev, 1991. 43(4): p.
475-505.
✤
Systemic alpha-2-adrenoceptor stimulation may facilitate inhibitory synaptic
responses in the superficial dorsal horn to produce analgesia mediated by
activation of the pontospinal noradrenergic inhibitory system Funai,Y., et al., Systemic
dexmedetomidine augments inhibitory synaptic transmission in the superficial dorsal horn through activation of descending noradrenergic control: an
in vivo patch-clamp analysis of analgesic mechanisms. Pain, 2014. 155(3): p. 617-28.
α-2-Adrenergic Agonists Clonidine vs Dexmedetomidine
• Dexmedetomidine has greater α2- versus α1- selectivity than
clonidine
• Postoperative neuropathic pain crisis
O'Neil T, Rodgers PE, Shultz C. Dexmedetomidine as
adjuvant therapy for acute postoperative neuropathic pain crisis. J Palliat Med. Oct 2014;17(10):1164-1166.
• Metaanalysis: Perioperative systemic alpha-2 agonists (clonidine or
dexmedetomidine) decrease postoperative opioid consumption, pain
intensity, and nausea. Recovery times are not prolonged. Common adverse
effects are bradycardia and arterial hypotension. Clonidine increased risk of
intraoperative (NNH 9) & postoperative hypotension (NNH 20).
Dexmedetomidine increased the risk of postoperative bradycardia (NNH 3)
Blaudszun G, Lysakowski C, Elia N, Tramer MR. Effect of Perioperative Systemic alpha2 Agonists on Postoperative Morphine Consumption and Pain
Intensity: Systematic Review and Meta-analysis of Randomized Controlled Trials. Anesthesiology. 2012 Jun;116(6):1312-22.
Clonidine
•
•
PO: 1-3 mcg/kg Q6h
•
IV : not FDA approved
Transdermal patch 4-12 mcg/
kg/day [patches: 0.1, 0.2 or
0.3 mg/day - occluding
smallest patch by 50%?]
•
•
1 mcg/kg/hr titrated to effect up to 3
mcg/kg /hr [Athens, Greece
5/16/2014];
•
Adult NHS Wolverhampton
Guidelines: starting dose 1 mcg/kg/h
[up to 4 mcg/kg/hr]
1mcg/kg Q6-8 hourly given over
15-20mins to reduce some of
dramatic blood pressure swings,
obviously we like to swap to orals
ASAP, the other [Sydney Children’s
Hospital, [email protected]
on 5/15/14]
Dexmedetomidine
•
•
•
Used in palliative care
Roberts SB, Wozencraft CP, Coyne PJ, Smith TJ. Dexmedetomidine as an adjuvant analgesic for intractable
cancer pain. Journal of Palliative Medicine. 2011 Mar;14(3):371-3. Soares LG, Naylor C, Martins MA, Peixoto G. Dexmedetomidine: a new option for
intractable distress in the dying. Journal of Pain and Symptom Management. 2002 Jul;24(1):6-8.
Children’s of MN: Dose 0.2-2 mcg/kg/hr IV
Rotation to clonidine:
•
•
•
0.1-0.6 mcg/kg/hr DEX = 1 mcg/kg/dose Q (4-) 6h CLONIDINE
0.7-1.4 mcg/kg/hr DEX = 2 mcg/kg/dose Q (4-) 6h CLONIDINE
1.5-2.0 mcg/kg/hr DEX = 3 mcg/kg/dose Q (4-) 6h CLONIDINE
Dexmedetomidine
✤
n=107 patients, age 3 days-17 years, retrospective review
✤
✤
✤
✤
Dexmedetomidine, as part of multi-modal management, appears to be
safe and efficacious; providing analgesia and sedation throughout all
pediatric age groups following cardiac surgery.
Overall well tolerated and safe with higher doses than previously
noted [0.8 µg/kg/hr to 2.17 µg/kg/hr]
Also well tolerated by neonates, infants, and patients with Trisomy 21
Withdrawal effects were noted in patients following prolonged
infusion. Horvath, R (1) Halbrooks, EF, Zielinski, EE, Lin, CW (2), Overman, DM (1), Friedrichsdorf, SJ (3), (4):Efficacy and safety of
postoperative dexmedetomidine administration in infants and children undergoing cardiac surgery: A retrospective cohort study. in Print 2015
J Ped Intensive Care
Dexmedetomidine in
Neonates
✤
Pharmacokinetics, safety, and
efficacy of dexmedetomidine in
preterm and term neonates at
three dose levels between 0.2 µg/
kg/hr and 0.5 µg/kg/hr: overall
effective for sedating this population
and it was well tolerated, different
overall PK profile compared to
older patients Chrysostomou, C, Schulman, SR,
•
Castellanos, MH, et al. (2013). A Phase II/III, multicenter, safety, efficacy,
and pharmacokinetic study of dexmedetomidine in preterm and term
neonates. Journal of Pediatrics. Pii:S0022-3476(13)01230-4.
Efficacy of fentanyl vs
dexmedetomidine in patients less
than 36 weeks gestational age at
birth who were less than 2 weeks
old at the study start and
mechanically ventilated. mean
duration 12.4 days, 0.3 - 1.2 µg /kg/
hour (mean 0.6), O’Mara, K, Gal, P,Wimmer, J, et al.
(2012). Dexmedetomidine versus standard therapy with fentanyl for
sedation in mechanically ventilated premature neonates. J Pediatr
Pharmacol Ther, 17(3): 252-262
Cannabis
San Diego, CA
•
•
AAP Handout for
parents "Despite
relaxed regulations,
marijuana harms
developing brain": http://
aapnews.aappublications.org/content/36/3/4.full.pdf
+html
Updated AAP policy
opposes marijuana
use, citing potential
harms, lack of
research http://
aapnews.aappublications.org/content/early/
2015/01/26/aapnews.20150126-1
Other Adjuvant Analgesic /
Co-analgesics
•
Muscle relaxants: Baclofen;
Cyclobenzaprine (Flexaril®)
•
Bisphosphonates: Osteoclast
inhibitors -> metastatic bone
pain Weinstein E, Arnold RM. Bisphosphonates for bone pain
•
adalimumab (Humira), certolizumab (Cimzia),
etanercept (Enbrel), infliximab (Remicade),
golimumab (Simponi).
#113. Journal of Palliative Medicine. 2010 Jul;13(7):893-4.
•
•
Antispasmodics: Hyoscine
butyl bromide (Buscopan®) [not
in USA], hyoscyamine
(Levsin®); oxybutynin
(Ditropan®), glycopyrrolate
(Robinul®)
β-ray emitting osteotrope radio
pharmaceutical: e.g.
Samarium-153-EDTMP
Anti-TNF α agent
[treatment of rheumatoid
arthritis (RA) and
spondyloarthropathies (SpAs)]
•
•
•
Back Pain
Kivitz, A.J., et al., Efficacy and safety of
tanezumab versus naproxen in the treatment of chronic
low back pain. Pain, 2013. 154(7): p. 1009-21.
Osteoarthritis Spierings, E.L., et al., A phase
III placebo- and oxycodone-controlled study of tanezumab
in adults with osteoarthritis pain of the hip or knee. Pain,
2013. 154(9): p. 1603-12.
Statins? Mouse: simvastatin,
rosuvastatin prevented injury
induced neuropathiv pain Shi XQ, Lim
TK, Lee S, Zhao YQ, Zhang J. Statins alleviate experimental nerve
injury-induced neuropathic pain. Pain. 2011 May;152(5):1033-43.
Botulinum toxin A
•
•
•
Peripheral neuropathic pain
6 RCTs: 50-200 units s.c. in
the region of pain
Low placebo effect
•
NNT: 1.9 [95% CI 1.5-2.5
for 4 studies]; one large
(unpublished) study
negative Finnerup NB, Attal N,
Haroutounian S, et al. Pharmacotherapy for
neuropathic pain in adults: a systematic
review and meta-analysis. The Lancet.
Neurology. Feb 2015;14(2):162-173.
E.T. May 2015 (22 kg)
•
•
•
•
•
•
•
•
PT, OT, IM
Celecoxib 50 mg BID PRN
Acetaminophen (Paracetamol) 352 mg Q6h PRN
Clonidine 100 mcg QHS plus 50 mcg PRN
Nortriptyline 16 mg QHS
Pregabaline 150 mg BID
Tramadol 20 mg Q4h PRN
[plus lactulose, senna, metoclopramide, Co Q10, riboflavin,
Potential Pain Pathologies
• Nociceptive Somatic Pain (Acute)
• Visceral Nociceptive Hyperalgesia
• Neuropathic Pain
• Chronic Pain (Pain beyond expected
time of healing)
•
Psycho-social-spiritual Pain
Metaanalysis 2011 (King et al.)
•
•
Chronic and recurrent pain
prevalent in children and
adolescents King S, Chambers CT, Huguet A,
MacNevin RC, McGrath PJ, Parker L, et al. The epidemiology of
chronic pain in children and adolescents revisited: a systematic
review. Pain. 2011 Dec;152(12):2729-38.
•
•
girls > boys
increasing with age
•
psychosocial variables
impacting prevalence:
anxiety, depression, lowself-esteem, other
chronic health
problems, lower socioeconomic status
Range
•
•
•
Headaches: 8-83 %
abdominal pain 4-53%
musculoskeletal (incl.
back) pain 4-49%
Primary Pain Disorder
• Chronic pain disorder that after
appropriate medical assessment
cannot be explained in terms of
conventionally defined medical disease
based on biochemical or structural
abnormalities
• Not typically responsive to
conventional medical therapy but
responsible for the consumption of
enormous medical resources
• Associated with significant
pain is not organic and therefore not
real or serious
disruption of everyday life and often
incapacitation
• Often pejorative implication, i.e.
•Neil L. Schechter, MD (Boston): Common and Confusing: Functional Pain
Syndromes in Children. Pediatric Pain Master Class, Minneapolis 2011
Primary Pain Disorders
• Chronic daily headache
• Dys-Functional
abdominal pain
• Chronic
musculoskeletal pain
(“fibromyalgia”)
• Majority of children
experience pain at
multiple sites
Chronic Pain
• Many different chronic and recurrent pain syndromes, in
both adult and pediatric populations, are now considered
manifestations of an underlying vulnerability rather than
separate disorders
• Opioids in the absence of tissue injury or inflammation
are contraindicated!
• Importance of rehabilitative, interdisciplinary team
approach
Potential Pain Pathologies
•
•
•
•
Nociceptive Somatic Pain (Acute)
Visceral Nociceptive Hyperalgesia
Neuropathic Pain
Chronic Pain (Pain beyond expected time of
healing)
• Psycho-social-spiritual Pain
Psycho-social-spiritual Pain
•
•
•
•
•
Change in environment
Change of routine
Increased caregiver stress/
anxiety
Loss of caregiver
“Pain in my heart”
Conclusions
• Episodes of inconsolability in
children with neurodevelopmental
delay are often multifactorial
• Neuropathic pain often underassessed and under-treated
• Treat underlying cause, if possible
and appropriate
• Careful step-by-step approach
(combining integrative,
rehabilitative, pharmacological and
interventional therapies) warranted
Further Training:
[email protected]
9th Annual Pediatric Pain Master Class • Minneapolis, MN | June 11-17, 2016
Education in Palliative & End-of-life Care [EPEC]: Become an EPECPediatrics Trainer
• 8th Conference: Montevideo, Uruguay | Sept 5, 2015
• 9th Conference: Chicago, IL | March 12-13, 2016
Twitter: @NoNeedlessPain
Stefan J. Friedrichsdorf, MD, FAAP Associate Professor of Pediatrics, University of Minnesota Medical School
Medical Director, Department of Pain Medicine, Palliative Care & Integrative Medicine Children's Hospitals and Clinics of Minnesota
2525 Chicago Ave S | Minneapolis, MN 55404 | USA
612.813.6450 phone | 612.813.7199 fax
[email protected]
Blog: http://NoNeedlessPain.org
http://www.childrensmn.org/services/painpalliativeintegrativemed